JP6294064B2 - 分子解析のための装置及び方法 - Google Patents
分子解析のための装置及び方法 Download PDFInfo
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Description
本願は、本明細書にその全体が全ての目的のために引用される、係属中である、2004年9月17日に出願された米国実用特許出願10/944,106の部分継続である。本願は、各々、全ての目的のために本明細書に引用される、2005年1月31日、2005年2月9日に出願された米国仮出願番号60/649,009及び60/651,846の優先権も請求する。
照射及びシグナル検出の閉じ込めは、蛍光相関分光法(FCS)の適用から、分子的診断における重要なツールとして長く認識されてきた。FCSは、フルオロフォア-標識分子を含む試料体積の照射、及び当該分子が有効観察体積に拡散したり有効観察体積から出たり時の、当該分子によって生成される蛍光シグナルのバラツキの検出を含む。観察下の体積が少数の蛍光分子のみを含む場合及びバックグランドシグナルが低い場合、蛍光強度のバラツキは、最も良く分析できる。これは、劇的に制限された観察体積と低試料濃度との組み合わせによって達成できる。典型的なFCSの検出体積は、約0.5フェトリットル(又は0.5 x 10-15リットル)であり、ぴったりとレーザービームに焦点を合わせるための高開口数顕微鏡対物レンズの使用により達成される。この検出体積において、単一分子は、最高約1ナノモーラーの濃度の溶液で観察できる。この濃度範囲は、典型的にマイクロモーラー範囲で又は上記のマイクロモーラー範囲である反応定数を有する、ほとんどの生化学的反応には許容されないほど低い。より低濃度では、これらの反応は、許容される速さで進行しないか、又はほとんどの分析で有用である形式とは定量的に異なった形式で進行する。単一分子をより高い、より関連する濃度で観察するために、観察体積は、典型的には、かなり小体積に限定される必要がある。
本発明の主な局面は、分子を特徴づけ及び/又は化学反応を監視するための光学システム及び方法のデザインである。本発明の装置及び方法は、特に単一-分子分析に適している。
当該外装材は、ゼロ-モード導波路のコアを介して縦方向にカットオフ波長未満の波長の電磁気エネルギーの伝達を除くように構成され、その際に、カットオフ波長未満の波長の電磁気的放射でゼロ-モード導波路を照射し、ゼロ-モード導波路は、個々の分子の分離を許容する有効観察体積を与える。ある局面では、有効観察体積は、ナノリットル((10-9リットル)未満、1ピコリットル未満、又は1フェトリットル未満、好ましくはゼプトリットルのオーダーである。本発明のゼロ-モード導波路を用いて、典型的には、100ゼプトリットル(100 x 10-21リットル)未満又は50ゼプトリットル又は更に10ゼプトリットルの有効観察体積を得ることができる。他の局面では、1ナノモーラー超、より一般的には100ナノモーラー超、好ましくはマイクロモーラーの範囲のオーダーの濃度で存在する個々の分子の分離を許容する有効観察体積を与える。好ましい実施態様では、約5マイクロモーラー超、7.5マイクロモーラー超又は更に50マイクロモーラー超の範囲の濃度で存在する個々の分子は、本発明の方法により分離することができる。
本発明の実施は、特に示さない限り、当該分野の技術内である、集積回路(IC)プロセシング生化学、化学、分子生物、ゲノミクス及び再結合DNAの慣用的な方法を採用することになる。例えば、Stanley Wolf他, SILICON PROCESSING FOR THE VLSI ERA, 第1-4巻 (Lattice Press); Michael Quirk他 SEMICONDUCTOR MANUFACTURING TECHNOLOGY; Sambrook, Fritsch and Maniatis, MOLECULAR CLONING: A LABORATORY MANUAL, 第2版 (1989); METHODS IN ENZYMOLOGY (Academic Press, Inc.)のシリーズ: PCR 2: A PRACTICAL APPROACH (MJ. MacPherson, B.D. Hames and G.R. Taylor著. (1995)を参照されたい。これらは本明細書に参照として引用されている。
明細書及びクレームに使用される、単数形「1つの(a)」、「1つの(an)」及び「その(the)」は、文脈が他に明確に特定しない限り、複数形を含む。
本発明の1つの局面は、分子を特徴付け及び/又は化学反応を監視するための光装置及び方法のデザインである。本発明の光装置は、生理学的に関連する条件下で膨大な数の単一-分子分析の多重化を可能にする。
かかる代替的な構造物は、特に限定されないが、反射率媒体を有する多孔質フィルム及び屈折率整合固体を用いる閉じ込めを含む。
合金は、金属性又は非金属性である各々の元素の含有量又は量が変化してもよい。好ましい合金は、一般的に、純粋な元素性材料を越える望ましい材料の特徴を改善する。材料の混合物の使用によって改善することができる特徴は、耐化学性、熱伝導率、電気的伝導率、反射率、粒径、熱膨張率、脆性、温度許容度、伝導率を含み、及び/又は外装の粒径を減少させる。
装置の好ましい実施態様は、1%未満のヒ素である金属フィルムを含む。装置のより好ましい実施態様は、0.1 %未満のヒ素である金属フィルムを含む。更により好ましい実施態様は、0.001 %未満のヒ素である金属フィルムを含む。更により好ましい実施態様は、0.00001 %未満のヒ素である金属フィルムを含む。別の好ましい実施態様は、1 %未満の鉛である金属フィルムを含む。別の好ましい実施態様は、0.1 %未満の鉛である金属フィルムを含む。別の好ましい実施態様は、0.01 %未満の鉛である金属フィルムを含む。別の好ましい実施態様は、0.001 %未満の鉛である金属フィルムを含む。別の好ましい実施態様は、0.00001 %未満の鉛である金属フィルムを含む。別の好ましい実施態様は、0.01 %未満の鉛である金属フィルムを含む。光閉じ込めの実施が特に重要な他の適用においては、伝導率を減少させる傾向にある不純物は、閉じ込めを悪化させ、望ましくないだろう。例えば、冶金の分野では、バナジウムは、アルミニウムの伝導率を減少させることが知られている。好ましい実施態様は、0.1 %未満のバナジウムである金属フィルムを含む。更により好ましい実施態様は、0.01 %未満のバナジウムである金属フィルムを含む。更により好ましい実施態様は、0.001 %未満のバナジウムである金属フィルムを含む。
コアは、典型的には、カットオフ波長(λc)未満の外側寸法を有する。径d及び完全導体のクラッドを有する環状ガイドに関して、λcは約1.7 x dである。コアの断面積は、環状、楕円形、長円形、円錐状、長方形、三角形、多面体又は任意の他の形状でよい。様々な形状が、ある適用のための具体的な適合性を有することができる。例えば、長い断面積は、機械的耐性又は剛性を有する分子、例えばDNAに増大した接近を提供するために有用であり得る。長い溝から様々な外観の長方形の割合までの範囲の断面は、放射線の軸方向の減衰において過度に妥協することなく、構造の検出域への難分解性分子の接近可能性を顕著に増大させるだろう。均一な断面積が好ましいが、その断面積は、必要ならばガイドの所与の深さが変動してもよい。好ましい平均断面積は、100 nm2〜10,000 nm2の範囲である。
消えていく放射線の細い領域は、低インデックス側のインターフェースに最も近接して確立される。この放射線は、典型的には、入射角及び2相の反射インデックスに依拠して、約100 nm〜約200 nmの範囲の減衰長を有する飛躍的に減少する領域である。低インデックス相が検体を含む溶液である場合には、消えていく放射線は、高度の表面感受性を溶液中の検体を試験するために使用することができる。
本発明はまた、本発明の光閉じ込めアレイを含むキットを包含する。本発明によって具体化されるキットは、分子を特徴付け及び/又は単一-分子レベルでの化学反応を監視することができるキットを含む。各キットは、通常、かかる特徴を与え及び/又は可能な手段を監視する装置及び試薬を含む。キットの意図した使用によって、キットの内容物及び包装は異なることになる。キットがDNAシーケンスのためである場合には、キットは、典型的に、以下を含む:(a) 個々の分子の分離又は個々の分子、例えば約1マイクロモーラー超の濃度で存在する分子、の反応を可能にする、光閉じ込めのアレイ、好ましくは本発明のゼロ-モード導波;及び (b) ポリメラーゼ、水溶性緩衝液、塩、プライマー、及びヌクレオチド又はヌクレオチドアナログを典型的に含むシーケンス試薬。必要であれば、公知の配列の「対照」核酸は、反応の精度又は進行を監視するために含まれる。
本発明のアレイは、本発明によって提供されるナノファブリケーション技術、並びに集積回路(IC)及び微小電気機械システム(MEMS)の分野で公知の技術を用いて製造することができる。ファブリケーションプロセスは、典型的には、アレイ基板を選択し、次いで光閉じ込め及び他の関連する部品を構築し一体化するために、好適なIC処理法及び/又はMEMSミクロ機械加工技術を用いて、進行する。
実施態様によっては、光閉じ込めのアレイは、硬い基板上に存在する。例えば反射インデックス媒体を有する多孔質フィルムに関する他の実施態様では、柔軟性材料を採用できる。一般的に、硬い支持体は、容易に曲がらない。本発明に関する硬い支持体でない固体材料の例は、膜、柔らかな金属又はプラスチックフィルム等を含む。従って、対象アレイの硬質基板は、アッセイが採用されるそのアッセイ条件下、特にハイスループット操作条件下で、物理的支持体及び構造をその上又はその中に存在する光閉じ込めに提供するには十分である。
対象アレイ基板の製造は、以下に記載の方法、又はIC-処理及び/又はMEMSミクロ機械加工の他の標準的技術に従って実行することができる。当該分野で公知の標準的技術は、特に限定されないが、電子-ビームリソグラフィー、フォトリソグラフィー、化学的蒸着又は物理的蒸着、乾式又は湿式エッチング、イオン注入、プラズマエッチング、結合及び電気メッキを含む。別の製造方法は、参考としてその全体が引用される、米国特許出願公開第2003/0174992号に記載されている。
光閉じ込め及び関連する光システムを含む対象装置は、分子を分析し及び化学反応をリアルタイムで監視するための効率的な手段を提供する。対象装置及び検出/監視法は、診断的及び研究的適用のための生化学的及び生物的反応の分析を含む様々な環境で使用することができる。特に好ましい局面では、本発明は、研究的適用のための核酸配列の解明において適用され、特に予防医薬の部分として個々のヒトゲノムをシーケンスすること、遺伝子型-表現型の関連のための迅速な仮定的試験、多-細胞生物の発達における全ての段階でのin vitro及びin situ遺伝子-発現プロファイリング、個々のクローン用の包括的な突然変異群を決定すること、及び様々な疾患又は疾患ステージでのプロファイリングに適用される。他の適用は、酵素反応速度論を測定し、標的分子と標的分子の候補モジュレーターとの間の特異的関係を特定することを含む。更なる適用は、細胞アクセプター多様性をプロファイルし、公知及び新規の病原を特定し、農業的、環境的及び治療的目標に向かって多様性を追及することを含む。
様々な形態の光閉じ込め及び関連する光システムを含む対象装置は、多重化単一-分子シーケンスに特に適している。従って、本発明は、多数の標的核酸を同時にシーケンスする方法を提供する。当該方法は、一般的に、(a) 本発明の光閉じ込めのアレイを提供し;(b) 多数の標的核酸分子、標的核酸分子に相補的なプライマー、重合化酵素、及び多数の新生ヌクレオチド鎖に取り込まれるべき1種以上のヌクレオド又はヌクレオチドアナログ、ここで各鎖は各々の標的核及び分子に相補的である、を閉じ込め内で混合し;(c) 当該混合物を、鋳型-指示重合による新生ヌクレオチド鎖の形成に好適な条件下で重合反応に供し;(d) 入射光ビームで導波路を照射し;並びに (e) 各新生的ヌクレオチド鎖に取り込まれるヌクレオチド又はヌクレオチドアナログを特定すること、を含む。
均一アッセイのある局面では、単一-分子のシーケンスは、次の塩基配列を読む前に混合物に反応物を添加しないで実行される。閉じ込め上の大体積の試薬からの反応物の拡散が取り込みの検出を邪魔であろうから、このアッセイでは、ヌクレオチドの段階的付加又は副生成物の除去は、必要でない。ポリメラーゼが好適なヌクレオチド又はヌクレオチドアナログを新生DNA鎖に頻繁に取り込むので、配列情報は連続して生じる。かかる単一分子シーケンスの詳細な議論に関しては、例えば、全ての目的のためにその全体が参照として本明細書に引用される公開された米国特許出願第2003/0044781号、及びMJ. Levene, J. Korlach, S.W. Turner, M Foquet, H.G Craighead, W W. Webb, SCIENCE 299: 682-686, January 2003 Zero-Mode Waveguides for Single-Molecule Analysis at High Concentrationsを参照されたい。単一分子は別個に観察されるので、同期化によるロスはない。この方法はまた、生物試料から直接的に採取された標的核酸分子の使用を可能にする。これは、シーケンスを行う前に、標的核酸のクローニング、サブクローニング又は増幅の必要性を最小限にする。
次いで、結合された(concatmerized)鎖は、単一鋳型としてシーケンスされ、重複情報はこの態様で単一分子から生じる。
本発明のシーケンス法を実施する際に、対象の標的核酸(複数)、標的核酸に相補的なプライマー、重合酵素及び1種以上のヌクレオチド又はヌクレオチドアナログを含む反応混合物は、光閉じ込めのアレイに適用される。好ましくは、各光閉じ込めは、配列される1つの標的核酸分子のみを受ける。これは、シーケンスプロセスに必要とされる反応物の残りを含む大体積の溶液中の少量の標的核酸を希釈することによって達成することができる。代替的には、開口部が側面積において基板よりも狭い非-円筒形の導波路は、複数の標的核酸の挿入を限定する原因となり得る。
標的核酸は、多数の方法により光閉じ込めの内面に固定することができる。例えば、標的核酸は、(1) プライマー又は (2) 単一-鎖標的核酸又は (3) 二重-鎖もしくは部分的二重-鎖標的核酸分子を結合することにより、光閉じ込め上に固定することができる。従って、(1) 標的核酸分子が、結合されたオリゴヌクレオチドプライマーにハイブリダイズされるか、(2) オリゴヌクレオチドプライマーが、固定された標的核酸分子にハイブリダイズされて、増幅された標的核酸分子複合体を形成するか、又は (3) (例えば、補助的タンパク質、例えばプライマーゼとの相互作用により)ポリメラーゼの認識部位が二重-鎖又は部分的に二重-鎖の標的核酸上につくられる、かのいずれかである。増幅された標的核酸分子複合体上の核酸重合酵素は、標的核酸分子に沿って動くために好適な、及び重合部位でオリゴヌクレオチドプライマーを伸張するために好適な位置で提供される。
単一-分子シーケンス法に従って利用した様々なヌクレオチドの種類は、検出可能な標識で複合化される。量子検出器が対象の光閉じ込め内のそれらの存在を検出し、識別することができるからである。好ましい標識は、発光標識、特に蛍光又は発色体標識である。
ある実施態様では、例えば、ヌクレオチドの塩基ユニットが修飾される。ある実施態様では、ヌクレオチド又はヌクレオチドアナログのリン酸基、好ましくは末端リン酸基、は、鋳型-指示重合反応の間に、より低度で新生核酸鎖に取り込まれる分子を与えるように修飾される。より好ましい実施態様では、ヌクレオチド又はヌクレオチドアナログの末端リン酸基は、鋳型-指示重合反応の間に、新生核酸鎖に実質的に取り込まれ得ない分子を与えるように修飾される。
例えば、クレアチンキナーゼ酵素は、アデノシド三リン酸からの1つのリン酸の除去に特異的であり、他の塩基には作用しないだろう。1種以上の非標識ヌクレオチドに選択的又は優先的に作用する他の酵素も使用できる。
トジヒドロ-スチルベン-2,2'-ジスルホン酸; 4,4'-ジイソチオチアネートジヒドロ-スチルベン-2,2'-ジスルホン酸; 5-[ジメチルアミノ]ナフタレン-1-スルホニルクロリド (DNS,ダンシルクロリド); 4-(4'-ジメチルアミノフェニルアゾ)安息香酸 (DABCYL); 4-dジメチルアミノフェニルアゾフェニル-4'-イソチオチアネート (DABITC); エオシン及び誘導体:エオシン、エオシンイソチオシアネート;、エリスロシン及び誘導体:エリトロシンB、エリトロシン、イソチオシアネート; エチジウム; フルオロセイン及び誘導体:5-カルボキシフルオレセイン (FAM)、5-(4,6-ジクロロトリアジン-2-イル)アミノフルオレセイン (DTAF)、2',7'-ジメトキシ-4',5'-ジクロロ-6-カルボキシフルオレセイン (JOE)、フルオレセイン、フルオレセインイソチオシアネート、QFITC (XRITC); フルオレサミン; IR144; IR1446; マラカイトグリーンイソチオシアネート; 4-メチルウンベリフェロン; オルト クレゾールフタレイン; ニトロチロシン; パラロサニリン; フェノールレッド; B-フィコエリトリン; o-フタルジアルデヒデド; ピレン及び誘導体:ピレン、酪酸ピレン、スクシンイミジル 1-酪酸ピレン; 酪酸エステル量子ドット;リアクティブレッド 4 (Cibacron. TM. ブリリアントレッド 3B-A)ローダミン及び誘導体:6-カルボキシ-X-ローダミン (ROX)、6-カルボキシローダミン (R6G)、リサミンローダミンB塩化スルホニルローダミン (Rhod)、ローダミンB、ローダミン123、ローダミンX イソチアシアネート、スルホローダミンB、スルホローダミン101、スルホローダミン101の塩化スルホニル誘導体 (Texas Red); N,N,N',N'-テトラメチル-6-カルボキシローダミン (TAMRA); テトラメチルローダミン; テトラメチルローダミンイソチアシアネート (TRITC); リボフラビン; ロソール酸;テルビウムキレート誘導体;Cy 3; Cy 5; Cy 5.5; Cy 7; IRD 700; IRD 800; La Jolla Blue; フタロシアニン; 及びナフタロシアニンを含む。
本発明のシーケンス方法は、鋳型-指示重合が重合酵素を用いて起こり得るような条件下で行われる。1つの局面では、重合酵素の基質、すなわちシーケンス反応に存在する様々な種類のヌクレオチドは、生理学的に関連する濃度に調整される。例えば、シーケンス反応に用いられるヌクレオチドは、ほぼ重合酵素のミカエリス定数の濃度で存在する。かかる濃度は、典型的には、約1マイクロモーラー〜約50マイクロモーラー又は約100マイクロモーラーの範囲である。
対象のシーケンス法は、光閉じ込め内に閉じ込められた個々の分子の画像を必要とする。ポリメラーゼ及び/又はヌクレオチドは、特定の種類のヌクレオチドが新生鎖に取り込まれるときに、識別可能な光シグナルを発光するフルオロフォアで標識される。ヌクレオチドが光閉じ込め内で新生鎖に連続的に付加されるので、識別可能なシグナルの配列が検出される。好ましい実施態様では、かかる検出は、各ヌクレオチド付加事象の後に、反応物もしくは副生成物(例えば、ヌクレオチドから開裂されるフルオロフォア)の移動、分離又は洗浄の必要なく実行される。この好ましい実施態様の1つの局面では、配列検出は、取り込まれるべき次の塩基配列ヌクレオチドを読む前に、混合物に反応物を加えることなく実行される。
対象の光閉じ込め及び光閉じ込めのアレイは、単一分子解析が望まれる多くの他の化学的及び生物的適用において有用性を見出す。一般的に、対象の光閉じ込めは、酵素、核酸、抗体、抗原等を含む、表面に結合することができ、基質を標識することができる任意の試薬を含む任意の単一分子解析に適用可能である。かかる適用は、生物分子、例えばタンパク質、糖タンパク質、核酸及び脂質:並びに無機化学物質、又はそれらの任意の組み合わせ、を含む識別可能な相互作用を含む。この相互作用は、核酸分子間、核酸とタンパク質間、及びタンパク質と小分子間でよい。
この実施態様の変更形式は、2つの分子が互いに結合する時に識別可能なシグナルを発光するドナー・フルオロフォア及びアクセプター・フルオロフォアで、標的及びプローブを標識する(又はその逆)ことである。適用可能なドナー・フルオロフォア及びアクセプター・フルオロフォアの範囲も、上に記載されている。当業者は、生物分子及び/又は化学化合物の特異的な相互作用の指標である識別可能なシグナルを生じるための、検出可能な標識及びその組み合わせの多様性を理解するだろう。
本発明の光閉じ込めは単一-分子解析を行う点で有用で特に有用であるが、対象の閉じ込めは、大量の測定群のハイスループット実行にも適している。従って、本発明は、多数の分子の間の相互作用を検出する方法であって、以下のステップ:ゼロ-モード導波路のアレイに非常に接近して多数の分子を置き、ここで、当該アレイ内個々の導波路は、光ビームの入射波長で当該アレイを照射した時に、多数の回折オーダーで散乱する検出可能な回折強度を与えるために十分な距離により分離される;入射波長でゼロ-モード導波路のアレイを照射し;及び、当該複数の回折オーダーで入射波長の回折散乱の強度における変化を検出し、それによって当該複数の分子間の相互作用を検出すること、を含む方法を提供する。
単一-分子シーケンスに適用可能な任意の構成は、この解析に等しく適する。
以下は、ゼロ-モード導波路の例証的製造方法を提供する。本明細書に記載のパラメータは、例にすぎず、任意の方法において限定するものではない。
2. 洗浄: 5部の脱イオン水、1部の(30% v/v 過酸化水素水)、1部の(30% v/v 水酸化アンモニア水)の混合物をホットプレート上で75℃まで加熱した。テフロン(登録商標)ホルダー又は他の化学抵抗性ホルダーを用いて混合物中にウェハを15分間浸漬した。
3. 濯ぎ: ウェハを含むホルダーをRCAクリーン浴から取り出し、脱イオン水浴に浸漬した。ウェハを2分間、この第二浴に放置した。ウェハを含むホルダーを当該浴から取り出し、脱イオン水でスプレイし、濯ぎプロセスを完了した。
4. 乾燥: 1分間の最終の濯ぎステップにおいて、ウェハを乾燥し、同時に、乾燥したきれいな窒素流を用いてホルダー内に維持した。
5. 酸素プラズマ: 次いで、ウェハをGlenn 1000pプラズマ・アッシャー中に置き、140 mTorrの圧、40kHz周波数での400ワットの前進的力で、プラズマエッチングモードで使用した(ウェハは、粉末状シェルフ上で、かつ別の粉末状シェルフの下に置いた)。プラズマを10分間維持した。分子状酸素の18 sccm流を使用した。
6. 蒸気操作(Vapor Priming): イールドエンジニアリングシステム(Yield Engineering Systems)蒸気操作オーブンにおいて酸素プラズマの後、ウェハを3分以内に装着した。ウェハは、ヘキサメチルジシラザン(HMDS)接着促進剤の層で被覆した。
7. 電子ビームレジストコーティング: NEB-31電子ビームレジスト(Sumitomo Chemical America)を用いるマニュアルスピナーユニット内で蒸気操作を行った後、ウェハを15分以内に被覆した。約3 mlをウェハ上に施行し、次いで60秒間、4500 rpmで回転した。初期加速及び減速は、3秒に設定した。
8. レジスト焼結: ウェハを115℃の温度で2分間、CEEホットプレート上で焼結した。プレートは、ウェハとホットプレート表面との良好な熱接触を可能にする真空構造に備えた。
9. 金蒸発: レジストで被覆された面上にある、10 nmの金層をウェハ上で熱蒸発させた。蒸発前に、2 10e-06 Torr未満の圧力に到達する必要がある。蒸発は約2.5オングストローム/秒の速度で行い、Inficonコントローラを用いて監視した。
10. 電子ビーム曝露: ゼロ-モード導波路からなるパターンは、高分解能の電子ビームリソグラフィー手段、例えばLeica VB6-HR装置を用いて、ウェハ上に曝露した。ゼロ-モード導波路は単一エクセル(exel)要素としてパターン化した。見掛1ナノアンペアの電流及び1の可変分解ユニットにおいて、5ナノメートルのエクセル設定に関して、10000マイクロクーロン/平方センチメートル〜300000マイクロクーロン/平方センチメートルの範囲でよい。
11. 後曝露焼結: 次いで、ウェハを、真空構造に同様に備えた、ホットプレート上で95℃で2分間、後曝露焼結に供した。
12. 金エッチング: 電子ビーム装置から除いた後、10ナノメートルの金層を、金腐食液TFAを用いて室温で、10秒間で除いた(GE 8148, Transene Corporation)。ウェハは、ステップ2で用いたものと同様のテフロン(登録商標)ホルダーに維持した。
13. 濯ぎ: ウェハを含むホルダーを金腐食液浴から取り出し、脱イオン水の浴に浸漬した。ウェハをこの第二浴中で、2分間以内、穏やかに手攪拌しながら放置した。ウェハを含むホルダーを当該浴槽から取り出し、脱イオン水でスプレイし、濯ぎプロセスを終了した。代替的に、ウェハを含むホルダーを、別の脱イオン水を含む新しい容器に入れた。
14. 乾燥: 1分間の最終の濯ぎステップにおいて、ウェハを乾燥し、同時に、乾燥したきれいな窒素流を用いて、ホルダー内に維持した。
15. 後曝露焼結: 次いで、ウェハを、真空構造に同様に備えた、ホットプレート上で95℃で2分間、後曝露焼結に供した。
16.現像:化学抵抗性のホルダー内のウェハを、現像剤MF-321 (Shipley Chemicals, Rohm-Haas)に室温で30秒間浸漬した。
17.濯ぎ:ウェハを含むホルダーを現像剤の腐食液浴から取り出し、脱イオン水の浴に浸漬した。ウェハをこの第二浴中で、2分間以内、穏やかに手攪拌しながら放置した。ウェハを含むホルダーを当該浴槽から取り出し、脱イオン水でスプレイし、濯ぎプロセスを終了した。
18.乾燥:1分間の最終の濯ぎステップにおいて、ウェハを乾燥し、同時に、乾燥したきれいな窒素流を用いて、ホルダー内に維持した。
19.表面ディスカミング処理:ウェハをアッシャリングモードでのGlenn 1000pプラズマ・アッシャー運転に装填した(ウェハは、粉末状プレートの下のベースプレート上にある)。140 mTorr圧の圧力及び40 kHzでの100ワット前進的力で、酸素プラズマをディスカミング処理する表面に30秒間供した。分子状酸素の18 scm流を使用した。
20.アルミニウム蒸発:ウェハを、表面ディスカミングプロセスの5分以内に、金属蒸発器内に装填した。100 nmの熱で蒸発したアルミニウム層は、ウェハ上に蒸着された。25オングストローム/秒の速度で2 x 10-6 Torr未満の圧力で蒸発させ、Inficonコントローラにより監視した。
21.アルミニウム厚測定: P-10 Profilometer (Tencor)で、アルミニウム厚を測定した。
22.ゼロ-モード導波路デキャスティング:ゼロ-モード導波路は、1165 Stripper (Shipley Chemicals, Rohm-Haas) 浴又はAZ-300T Stripper (Shipley Chemicals, Rohm-Haas) 浴中で、テフロン(登録商標)ホルダー又は他の化学的抵抗性ホルダーにそれらを浸漬することにより、包含されるアルミニウムフィルムからデキャストした。当該浴槽は、超音波装置にStripper及びウェハホルダーを維持する容器を浸漬することにより、超音波に供した。ウェハを30分間又は約45分間超、デキャスティング浴に放置し、追加的に穏やかに攪拌した。
23.濯ぎ:剥離浴を、超音波から取り出した。ウェハを剥離剤(stripper)浴から取り出し、脱イオン水の浴槽に漬けた。ウェハをこの第二浴に2分間、穏やかに手攪拌しながら放置し、ウェハを当該浴から取り出し、脱イオン水でスプレイし、濯ぎプロセスを完了した。
24 乾燥:1分間の最終の濯ぎステップにおいて、ウェハを乾燥し、同時に、乾燥したきれいな窒素流を用いてホルダー内に維持した。
25.フォトレジストコーティング:ウェハを、1500 rpmの速度で、Shipley 1827フォトレジストスパンで被覆した。約5mlのレジストを散布した。加速及び減速を5秒に設定した。
26.レジスト焼結:115℃の温度で15分間、ウェハをCEEホットプレート上で焼結した。
プレートは、ウェハとホットプレート表面との間に良好な熱接触を可能にする真空構造を備えた。
27.ダイシング:ウェハを、樹脂/ダイアモンド刃 (ADT 00777-1030-010-QIP 600) により、K&S-7100ダイシングソー(dicing saw) (Kuhcke & Soffa) を用いて切断した。ダイシング前に、ウェハを低-タック接着テープ上に置いた。
28.ダイ除去:ダイを接着テープから手でとり、保存した。
29.レジスト除去:ダイを最初にアセトン浴に1分間浸漬し、次いで2-プロパノー浴に2分間、穏やかに手攪拌しながら浸漬することにより、1827フォトレジスト層を除いた。
30.ダイ乾燥:乾燥したきれいな空気を用いて2-プロパノール浴を取り出した後、ダイを乾燥した。
31.プラズマ洗浄:ウェハをDrytek 100プラズマエッチャーに装填し、140 mTorrの圧力で酸素状プラズマ、85 sccm酸素の分子状酸素流、及び13 Mhzでの500ワット前進的力のRF力に1分間供した。代替的に、Harrick Plasma Cleaner PDC-32Gを、2 Torrの圧力及び10.5ワットで、乾燥したきれいな空気プラズマに5分間供した。
単一DNAポリメラーゼ分子によるDNA鎖の酵素合成のリアルタイムでのモニタリング
この実験は、光システム及び以下に詳述する反応混合物を用いて、行うことができる。
しかしながら、任意の特定の光システム及びパラメータについての文献、緩衝剤、試薬。
濃度、pH、温度等は、限定されるものではない。それらは、本発明の方法を実行する1例として提供するために含まれる。
複数の異なった標識ヌクレオチドを用いるリアルタイムシーケンス
2つの異なった標識ヌクレオチドアナログを用いて、上記の実施例2に記載の実験と同様の実験を行った。実験は、光セットアップ又はシステム及び以下に詳述する反応混合物を用いて行った。しかしながら、任意の特定の光セットアップ及びパラメータに関する文献、緩衝剤、濃度、pH、温度等は限定されるものではない。それらは、本発明の方法を実施する1例として提供するために含まれる。
Claims (17)
- 環状単一核酸分子内の連続するヌクレオチド配列を決定する方法であって、以下:
a)環状単一核酸分子を提供し;
b)当該環状単一核酸分子を鋳型-指示重合反応に供することによって、当該環状単一核酸分子内の連続するヌクレオチドの反復シーケンスを実行すること、ここで、当該反復シーケンスは、当該環状単一核酸分子内の連続するヌクレオチドを当該環状単一核酸分子の鋳型-指示重合反応中に複数回シーケンスし、それによって当該環状単一核酸分子の連続するヌクレオチドの複数の読みを生成することを含む;及び
c)当該複数の読みを分析して、環状単一核酸分子内の連続するヌクレオチド配列を決定すること、
を含む、方法。 - 前記の連続するヌクレオチド配列が、環状単一核酸分子中に1回存在する、請求項1記載の方法。
- 前記の環状単一核酸分子が、鋳型-指示重合反応中に1回超シーケンスされる、請求項1記載の方法。
- 前記の複数の読みが、環状単一核酸分子で鋳型-指示重合反応中にリアルタイムでステップb)で生成される、請求項1記載の方法。
- 前記の複数の読みが、少なくとも1塩基/秒の速度で生成される、請求項1記載の方法。
- 複数種のヌクレオチド又はヌクレオチドアナログの存在下で行われ、前記ヌクレオチド又はヌクレオチドアナログの各種が標識を有する、請求項1記載の方法。
- 前記標識が、三リン酸、四リン酸、五リン酸及び六リン酸からなる群より選ばれるリン酸部分の末端リン酸の位置にある、請求項6記載の方法。
- 前記生成が、環状単一核酸分子を含む単一複合体を含む光閉じ込め中で行われる、請求項1記載の方法。
- 前記光閉じ込めがゼロ-モード導波路である、請求項8記載の方法。
- 核酸シーケンス法であって、
a)環状標的核酸分子を鋳型-指示重合反応に供して、多数の種類のヌクレオチド又はヌクレオチドアナログの存在下で当該環状標的核酸分子に相補的である新生核酸鎖を得ること、ここで、当該鋳型-指示重合反応が当該環状核酸分子内のヌクレオチド配列を複数回処理する;
b)当該環状単一核酸分子の鋳型-指示重合反応中にヌクレオチド又はヌクレオチドアナログからの塩基の新生核酸鎖への取り込みの時間系列を登録すること、それによってヌクレオチド配列のための複数の配列読みを生成する;及び
c)当該複数の読みを分析して、当該環状標的核酸分子内のヌクレオチド配列を決定すること、
を含む、方法。 - 前記ヌクレオチド又はヌクレオチドアナログが標識を更に含む、請求項10記載の方法。
- 前記標識が、三リン酸、四リン酸、五リン酸及び六リン酸からなる群より選ばれるリン酸部分の末端リン酸の位置で、ヌクレオチド又はヌクレオチドアナログに結合される、請求項11記載の方法。
- 前記ヌクレオチド又はヌクレオチドアナログの各種が、前記登録ステップで、互いに識別される異なった標識を有する、請求項11記載の方法。
- 前記登録が、鋳型-指示重合反応が進行している間に行われる、請求項10記載の方法。
- 前記鋳型-指示重合反応が、少なくとも1つの塩基/秒の速度で処理する、請求項10記載の方法。
- 前記鋳型-指示重合反応が光閉じ込めで起こる、請求項10記載の方法。
- 前記閉じ込めがゼロ-モード導波路である、請求項16記載の方法。
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WO2006044078A3 (en) | 2008-02-21 |
US20060062531A1 (en) | 2006-03-23 |
EP1790202A4 (en) | 2013-02-20 |
JP2014057601A (ja) | 2014-04-03 |
AU2005296200A1 (en) | 2006-04-27 |
US7315019B2 (en) | 2008-01-01 |
AU2005296200B2 (en) | 2011-07-14 |
CN101914620B (zh) | 2014-02-12 |
GB0608338D0 (en) | 2006-06-07 |
EP3415641B1 (en) | 2023-11-01 |
EP3415641A1 (en) | 2018-12-19 |
US7476503B2 (en) | 2009-01-13 |
US20060063264A1 (en) | 2006-03-23 |
EP1790202A2 (en) | 2007-05-30 |
US20060061754A1 (en) | 2006-03-23 |
US7302146B2 (en) | 2007-11-27 |
JP2008513782A (ja) | 2008-05-01 |
GB2423819A (en) | 2006-09-06 |
CA2579150C (en) | 2014-11-25 |
CN101914620A (zh) | 2010-12-15 |
US20060061755A1 (en) | 2006-03-23 |
WO2006044078A2 (en) | 2006-04-27 |
CA2579150A1 (en) | 2006-04-27 |
GB2423819B (en) | 2008-02-06 |
JP2016154560A (ja) | 2016-09-01 |
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